(ChemotherapyAdvisor) – Intermittent dosing might delay or prevent the development of vemurafenib resistance and drug-dependent tumor growth in patients with melanoma, according to authors of a cohort study presented at the American Association for Cancer Research (AACR) Annual Meeting 2013, in Washington, DC.

“It was exciting to witness the discovery of BRAF mutations in melanoma and the translation of this discovery into an effective therapy with vemurafenib,” said senior author Darrin D. Stuart, PhD, at the Novartis Institutes for Biomedical Research in Emeryville, CA. “It was, however, disappointing to see patients stop responding to such a promising therapy after 6 to 8 months of treatment.”

BRAF oncoprotein mutations are the most prevalent known genetic alteration in human melanomas, with more than half of melanomas harboring these alterations, Dr. Stuart noted. Previous mouse studies of patient-derived melanoma with BRAF mutations showed that tumors that developed vemurafenib resistance became dependent on the drug for tumor growth.

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Following up on the animal study, Dr. Stuart and his colleagues evaluated 42 patients with vemurafenib-resistant tumors, using computed tomography scan images of tumors from after vemurafenib cessation (n=19).

Of these 19 patients, 14 exhibited a decrease in tumor growth rates, Dr. Stuart reported.

“This is the first evidence that the drug-addicted state that we observed in our mouse models may also occur in humans,” Dr. Stuart noted.

It is possible that intermittent dosing might avoid the development of vemurafenib resistance in tumors, Dr. Stuart and his colleagues argued. In mice implanted with human-derived tumors and treated with vemurafenib either continuously or intermittently, with 4 weeks on and 2 weeks off, none of the tumors in the intermittent dosing group developed drug resistance, they reported. 

Results “suggest that altered dosing might delay or prevent the emergence of lethal drug resistant disease,” Dr. Stuart reported.

“Continuous dosing maintained the selective pressure required for the few surviving tumor cells to develop resistance, and alternating the selective pressure through intermittent dosing appeared to prevent the evolution and expansion of resistant cells,” he explained. “This study provides insight into how vemurafenib-resistant tumors evolve. Alternative dose regimens could prolong the durability of response to vemurafenib in BRAF-mutant melanoma.”

Abstract (#LB-144)